PROJECT SUMMARY/ABSTRACT Background/Significance: The global burden of low birth weight (LBW, <2500 grams) has not changed significantly with interventions targeted at traditional risk factors; twenty million infants continue to be born LBW each year, increasing their risks of newborn mortality, childhood stunting, and chronic adult disease. To achieve the World Health Organization's ambitious target of reducing LBW by 30% by 2025, novel risk factors must be identified, particularly in low/middle income countries where >95% of LBW infants are born. Prenatal environmental exposures are potential modifiable contributors to LBW but have been underexplored in LMICs. Objectives/Aims: We will evaluate exposure to organophosphate pesticides (OPs) during pregnancy and determine its association with LBW in rural sub-Saharan Africa where one in six newborns is LBW. We propose three aims: 1) To characterize exposure to OPs and identify predictors of high exposure that may be targeted in future exposure reduction efforts; 3) To determine the association of OP exposure with newborn weight and gestational age at birth, the two contributors to LBW; and, 3) To evaluate the association between OP exposure and placental injury, a potential target organ for OP toxicity that may mediate the effect of OP exposure on birth outcomes. Methods: We will leverage an existing birth cohort derived from the Ghana Randomized Air Pollution and Health Study (GRAPHS) in which 1,414 pregnant women were enrolled prior to 28 weeks gestation and assigned to distinct prenatal cooking strategies. The cooking interventions had no impact on birth weight, gestational age at birth, or other obstetric outcomes; however, an extensive biobank of maternal urine specimens and placental tissue was created and, in combination with detailed covariate data and rigorously collected birth outcomes, provides a rich platform to address our questions about OP exposure and LBW. We will measure concentrations of specific OP biomarkers in repeated maternal urine samples (4 per pregnancy) to evaluate our hypotheses. Our exposure-response analysis will be augmented with evaluation of placental tissue to highlight potential mechanisms of prenatal OP injury. Innovation: This study is the first to evaluate prenatal OP exposure and LBW in rural Africa, where pesticide exposure is high and one in six newborns is LBW. We will overcome methodologic limitations of prior literature from industrialized settings with access to repeated prenatal urine samples to better characterize exposure, a large sample size and extensive covariate data and will employ innovative statistical approaches to address mixtures of pesticide exposures and estimate windows of susceptibility. Our study will also be the first to integrate evaluation of the placenta into investigation of the impacts of prenatal OP exposure. 1